6alpha-trifluoromethyl substituted steroids of the 5alpha,5beta,and delta**4-pregnane series



United States Patent O 3,457,259 Ga-TRIFLUOROMETHYL SUBSTITUTED STEROIDS OF THE 501,515, AND A -PREGNANE SERIES John H. Fried, Palo Alto, Calif., assignor to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed June 27, 1966, Ser. No. 560,865 Int Cl. C07c 169/30, 173/00, 169/36 U.S. Cl. 260-23955 13 Claims ABSTRACT OF THE DISCLOSURE 6a-trifluoromethyl substituted steroids of the Star, 513- and A -pregnane series.

and CF3 Or the group Patented July 22, 1969 R represents hydrogen, hydroxy or a carboxylic acyloxy group of less than 12 carbon atoms; R represents a carbonyl group or the group OR o and R represents a carbonyl group or the group wherein R represents hydrogen, a carboxylic acyl group of less than 12 carbon atoms, tetrahydropyran-2'-yl, or tetrahydrofuran-2-yl; and R represents the group or the group (ORII wherein R" represent tetrahydropyran-2'-yl or tetrahydrofuran-2-yl.

The carboxylic acyl and acyloxy groups of the compounds of the present invention contain less than 12 carbon atoms and may be of a straight, branched, cyclic or cyclic-aliphatic chain structure. This structure may he saturated, unsaturated, or aromatic and optionally substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno, and the like. Typical esters thus include acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, arninoacetate, fi-chloropropionate, adamantoate, and the like.

The novel compounds of the present invention represented by Formulas A and B above are prepared according to the following illustrated process.

"OX0 cF e c=o From The novel compounds of the present invention rep- H resented by Formula C above, are prepared according to In the above formulas R is as defined hereinabove and R represents a carboxylic acyloxy group of less than 12 carbon atoms, tetrahydropyran-2-yloxy or tetrahydrofuran-2-yloxy.

In practicing the process outlined above, the starting material I, 6a-trifluoromethylpregn-4-cue-3,20-dione, 6oztri fluoromethyl 17a hydroxypregn 4 ene 3,20- dione 17 acylate, e.g. 17 acetate, or 60: trifluoromethyl 17a hydroxypregn 4 ene 3,20 dione (disclosed in United States application Ser. No. 68,376, filed Nov. 10, 1960, now US. Pat. No. 3,328,431 is reacted with hydrogen over a platinum oxide catalyst to furnish a mixture of the 3a-hydroxy-5fl-derivative (II) and the 3,8-hydroxy-5a-derivative (II) which are separated by chromatography. The 3-hydroxy compounds (II and II) are oxidized as by treatment with, e.g., chromium trioxide in pyridine to yield the novel 3-oxo compounds of the present invention. By treatment of the 3-hydroxy steroids (II or II) with dihydropyran or dihydrofuran in the presence of p-toluenesulfonyl chloride, the corresponding 3 tetrahydropyran 2' yloxy and 3 tetrahydrofuran- 2'-yloxy compounds (III and III; R is tetrahylropyran- 2'-yl0xy or tetrahydrofuran-Z'-yloxy) are obtained. Alternatively, the steroids II and II are acylated as by treatment with a carboxylic acid anhydride, e.g. acetic anhydride, propionic anhydride and the like, in pyridine or a carboxylic acid halide to furnish the novel 3ot-acyloxy- 5(3- and 3 ,B-acyIoxy-Sa-deriVatiVes of the present invention (III and III, R is acyloxy).

By treatment of the steroids II, II, III and III with, e.g. sodium borohydride in methanol for a period of time of the order of about 16 hours or more, the 20-oxo group is reduced to the corresponding free alcohol to furnish a mixture of the ZOOL-hYdYOXY and 20,8-hydroxy derivatives from which the 20,8-hydroxy compounds of the present invention can be separated.

the following outlined process.

a: c=o

O (I) y cu c a l, l 3 i c'= c=o .R

In the above formulas, R and R" are as defined hereinabove.

In practicing the above outlined process, the 3-keto-A starting material I is reacted with sodium borohydride or lithium tri-t-butoxyaluminum hydride in an organic solvent such as methanol, ethanol, tetrahydrofuran, doxane, and the like to furnish a mixture of the corresponding 3 tZ-hydroxy-A and 3ot-hydroxy-A derivatives IV and IV, respectively which are separated by chromatography. The 3-hydroxy derivatives are converted into the corresponding 3-tetrahydropyran-2-yl ether or 3-tetrahydrofuran-2'-yl ether (V and V) by treatment with dihydropyran and dihydrofuran, respectively, in the presence of a catalyst such as p-toluenesulfonyl chloride.

The following examples serve to illustrate but are not intended to limit the scope of the present invention.

Example I A solution of 2.0 g. of 6ot-trifiuoromethyl-Not-hydroxypregn-4ene-3,20-dione-17-acetate is hydrogenated with 0.1 g. of platinum oxide catalyst until the theoretical amount of hydrogen is consumed. The catalyst is removed by filtration and the filtrate is evaporated to dryness to yield a mixture of 3a,17tat-dihydroxy-6u-trifluoromethyl- 5,8 pregnan 20 one 17 acetate and 3fl,17oc dihydroxy 60c trifluoromethyl 55 pregnan 2O one- 17-acetate which are separated by chromatography on alumina eluting with benzene-ether, ether and then ethermethanol.

By repeating the foregoing process using Gzx-tI'iflUOIO- methylpregn 4 ene 3,20 dione and 6a trifiuoromethyl 17cc hydroxypregn 4 ene 3,20 dione as the starting material, there is obtained 3a-hydroxy-6a-trifluoromethyl 5B pregnan 20 one, 35 hydroxy 6atrifluoromethyl 5oz pregnan 20 one, 30:, 17a di hydroxy 60c trifluoromethyl 5B pregnan 20 one and 3 3,17 dihydroxy 6a trifiuoromethyl 50cpregnan-20ot-one, respectively.

Example 2 A mixture of one gram of 30a, l7a-dihydroxy-6u-trifluoromethyl 55 pregnan 20 one 17 acetate, 1 g. of potassium hydroxide in 10 ml. of water, and 90 ml. of methanol is refluxed for one hour. At the end of this time, the methanol is evaporated under reduced pressure and the residue is extracted with ethyl acetate and water. Evaporation of the ethyl acetate from these extracts yields 30:,1701. dihydroxy 6oz trifiuoromethyl 55 pregnan- 20-one which is collected by filtration and recrystallized from acetone: hexane.

By use of this process, 3,8,17a-dihydroxy-6a-trifluoromethyl-5u-pregnan20-one-17-acetate is converted into 3,3,17oc dihydroxy 60c trifluoromethyl 5m pregnan- 20-one.

Example 3 A solution of 6 g. of 3a,l7a-dihydr0xy-6u-trifiuoromethyl-5fl-pregnan-20-one-17-acetate in 120 ml. of pyr idine is added to a mixture of 6 g. of chromium trioxide in 20 ml. of pyridine. The reaction mixture is allowed to stand at room temperature for hours, diluted with ethyl acetate and filtered through Celite diatomaceous earth. The filtrate is washed well with water, dried and evaporated to dryness to yield l7a-hydroxy-6ix-trifiuoromethyl-55-pregnane-3,20-dione-17-acetate which may be further purified by recrystallization from acetone:hexane.

By repeating the process of this example using the other 3-hydroxy compounds of this invention, there is obtained 170a hydroxy 6oz trifluoromethyl 5 0c pregnane 3,20- dione 17 acetate, 60c trifiuoromethyl 55 pregnanc- 320, dione, 6a trifluoromethyl 50c pregnane 3,20- dione, 17oz hydroxy 6a trifiuoromethyl 5,8 pregnanc- 3,2O dione and 17a hydroxy 60c trifiuoromethyl- 5a-pregnane-3,20-dione.

Example 4 Two milliliters of dihydropyran are added to a solution of 1 g. of 3a,17a-dihydroxy6a-trifiuOrOmethyI-SB-pregnan-20-one-17-acetate in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonyl chloride is added to the cooled solution. This mixture is allowed to stand at room temperature for four days, and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield 3a-(tetrahydropyran-2'-yloxy)17uhydroxy 6a trifluoromethyl 5,8 pregnan 20 onel7-acetate which is recrystallized from pentane.

By using as the starting material in the process of this example, the other 3-hydroxy compounds of the present invention, the corresponding 3-tetrahydropyran-2-yl ether is obtained, e.g. 3a-(tetrahydropyran-2'-yloxy)-17a-hy droxy 60c trifluoromethyl 5B pregnan 2O one and 30a (tetrahydropyran 2' yloxy) 60c trifiuoromethyl- 5/8-pregnan-20-one.

Example 5 To a solution of 1 g. of 3a,17a-dihydroxy-6a-trifluoromethyl-5,B-pregnan-20-one-17-acetate in 20 ml. of benzene, 20 m1. of dihydrofuran is added. Five milliliters is distilled off to remove moisture, and the mixture is allowed to cool to room temperature. To the coo-led mixture, 0.2 g. of freshly purified p-toluenesulfonyl chloride is added. The mixture is stirred at room temperature for 24 hours and then poured into an excess of 5% aqueous sodium bicarbonate solution. The product is extracted with ethyl acetate, the organic solution is washed with water to neutral, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The residue crystallizes on the addition of ether to yield 304 (tetrahydrofuran-2'-yloxy)-17a-hydroxy-6a-trifiuoromethyl-5B-pregnan-20-one-17-acetate.

By repeating the above procedure using as the starting material 3a,l7a dihydroxy- 6a-trifluoromethyl-Sfi-pregnan 20 one, 3,8,17a-dihydroxy-6wtrifiuOromethyI-Sapregnan 20 one 17-acetate, 3fi-hydr0xy-6a-trifluoromethyl-5a-pregnan-20-one, and 3fi,l7a-dihydroxy-6a-trifluoromethyI-Sa-pregnan-ZO-one, there are obtained the corresponding 3-tetrahydrofuran-2-y1 ethers.

Example 6 A mixture of 1 g. of 3a,17a-dihydroxy-6u-trifluoro- .methyl Sfi pregnan-ZO-one-l7-acetate, 4 ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration washed with water and dried to yield 3a17oz-dihydroxy 60c trifluoromethyl 5,8-pregnan-20-one-3-l7-diacetate which may 'be further purified through recrystallization from acetone:hexane.

By repeating the above process using other 3-hydroxy compounds of the present invention as the starting material the corresponding 3-acetate is obtained, e.g., 3ot-hydroxy 6a trifiuoromethyl-S/B-pregnan-ZO-one-3-acetate, 35 hydroxy 6a-trifiuoromethyl-5a-pregnan-20-one-3- acetate, 3,8,17dihydroxy-6a-trifiuoromethyl-Sat-pregnan- 20-one-3,l7-diacetate Similarly, by using other carboxylic acid anhydrides in the process of this example, other 3-acylates are obtained, e.g. 3-propionate, 3-trichloroacetate, and the like.

Example 7 A mixture of 1 g. of 3a-(tetrahydropyran-2-yloxy)- 17a hydroxy 6ot-trifiuoromethyl-SB-pregnan-ZO-one-17- acetate and 1 g. of potassium hydroxide in 10 ml. of water and m1. of methanol is refluxed for one hour. At the end of this time, the methanol is evaporated under reduced pressure and the residue is extracted with ethyl acetate and water. Evaporation of the ethyl acetate from these extracts yields 3a-(tetrahydropyran-2-yloxy)-17ahydroxy 6a trifluoromethyl-SB-pregnan-ZOpne which is collected by filtration and recrystallized from acetone: hexane.

Similarly, 3oz (tetrahydrofuran-2-yloxy)-6a-trifiuoromethyl a hydroxy-5B-pregnan-20-one-17-acetate, 3,8- (tetrahydropyran 2' yloxy) 6oz trifluoromethyl-17ahydroxy-5a-pregnan-20-one-l7-acetate, and 3B-(tetrahydrofuran 2' yloxy)-6a-trifiuoro1nethyl-17a-hyd-roxy-5atpregnan-ZO-one-17-acetate are converted into the corresponding 17-free alcohol.

Example 8 A mixture of 1 g. of 3a,17a-dihydroxy-6a-trifluoromethyl-Sfi-pregnan-20-one, 1 g. of p-toluenesulfonic acid monohydrate, 50 ml. of caproic acid and 25 ml. of caproic anhydride is allowed to stand at room temperature for 24 hours, and then poured into water and stirred. This mixture is then extracted with methylene chloride and these extracts are dried and evaporated to yield 3a, 170a dihydroxy 6a-triiiuoromethyl-SB-pregnan-20-one-3, 17-dicaproate which is recrystallized from acetonezether.

Similarly, 35,170: dihydroxy 6a-trifiuoromethyl-5otpregnan-ZO-one is converted into 3,6,17oz-dihyd1OXy-6zxtrifiuoromethyl-u-pregnan-20-one-3,17-dicapr0ate.

Likewise, by the use of other acids and anhydrides, e.g. valeric acid and valeric anhydride, propionic acid and propionic anhydride, and the like in the process of this example, the corresponding diacylates are obtained, e.g. 3,17-divalerate, 3,17dipropionate, and the like.

Example 9 One gram of 3a,17a-dihydroxy-6u-trifiuoromethyl-5 3- pregnan-20-one-3,l7-dicaproate is allowed to stand at room temperature for 5 hours with 0.25 grams of potassium hydroxide in ml. of water and 90 ml. of methanol. At the end of this time, the methanol is evaporated under reduced pressure and the residue is extracted with ethyl acetate and water. Evaporation of the ethyl acetate from these extracts yields 3u,17u dihydroxy 6a trifluoro methyl-Sfi-pregnan-ZO-one-17-caproate which is collected by filtration and recrystallized from acetonezhexane.

In a similar manner, the other 3,17-diacylates of the present invention are converted into the corresponding 3- hydroxy-17-acylate derivatives.

By use of the process of Example 4, 3a,17adihydroxy- 6a-trifluoromethyl-SB-pregnan-ZO-one-17-caproate is converted into 3a-(tetrahydr0pyran-2'-yl0xy)-17ot-hydroxy- 6oz trifiuoromethyl-SB-pregnan-ZO-one-17-caproate. Similarly, by the use of the process of Example 5, 3a-(tetrahydrofuran 2 yloxy) 17a-hydroxy-6a-trifluoromethyl- 5fl-pregnan-20-one-17-caproate is obtained from 30,l7adihydroxy 60c trifluoromethyl 5B-pregnan-20-one-l7- caproate.

Example 10 A mixture of 1 g. of 6oz-tfiflu01'01'll6thYl-17oc-hYdI'OXY- pregn-4-ene-3,20-dione-17-acetate and 1 g. of lithium trit-butoxy-aluminum hydride in 50 ml. of tet-rahydrofuran is allowed to stand at about C. for twenty four hours. Thereafter, the mixture is evaporated under reduced pressure and the residue is crystallized in acetone1hexane to furnish 3fi,17u dihydroxy-6a-trifluoromethylpregn-4-en- 20 one l7-acetate. The mother liquors are chromatographed over alumina eluting with benzene-ether, ether and ether-methanol to furnish 3a,170c-dllhydIOXy-6cc-Uifluoromethylpregnl-en-2O-one-l7-acetate and additional 35,170; dihydroxy 6oz trifluoromethylpregn 4-en-20- one-l7-acetate.

By repeating the process of this example using as the starting material, 60: trifluoromethylpregnt ene-3,20- dione and 60: trifluoromethyl-1'7u-hydroxypregn-4-ene- 3,20-dione, there is obtained 3a-hydroxy-6m-trifiuoromethylpregn -4-en-20-one, 36 hydroxy 6a trifluoromethylpregn-4-en-20-one, 30:,170: dihydroxy 6a: trifiuoromethylpregn-4-en-20-one and 3B,17o-dihydroxy-6u trifluoromethylpregn-4-en-20-one, respectively.

Example 11 By using 3,3,17a-dihydroxy-6wtrifluorornethylpregn-4- en-20-one-l7-acetate as the starting material in the process of Example 4, there is obtained 3,8-(tetrahydropyran- 2-yloxy)-17or-hydroxy-6a-trifluoromethylpregn 4 en- 20-one-17-acetate.

Similarly, by subjecting the other 3-hydroxy-A compounds of Example 10 to the procedure of Example 4, the corresponding 3 tetrahydropyran-2-yl ethers are obtained.

Example 12.

By repeating the procedure of Example 5 using as the starting material, the 3-hydroxy-A compounds of Example 10, the corresponding 3-tetrahydrofuran- 'y1 ethers are obtained, eg. 36- (tetrahydrofuran-2-yloxy)- l7a-hydroxy 6a trifluoromethylpregn-4-en-20-one-17- acetate and 3a- (tetrahydrofuran-2'-yloxy)17a-hydroxy- '6a-trifluoromethylpregn-4-en-20-one-17-acetate.

Example 13 A solution of 1 g. of sodium borohydride in 3 ml. of water is added to an ice-cooled solution of 1 -g, of 3a- (tetrahydropyran-2-yloxy)-17 x-hydroxy 6a trifiuoromethyl-Sfi-pregnan-ZO-one-l7 acetate in ml. of methanol and the mixture is then allowed to stand for 16 hours at room temperature. The excess reagent is decomposed by addition of acetic acid and the solution is then concentrated to small volume in vacuo and diluted with water. The product is extracted with ethyl acetate and these extracts are washed with water, dried and evaporated. The crude mixture is then separated by chromatography on silica gel to furnish 3a-(tetrahydropyran-2'- yloxy)-6a-trifiuoromethyl 5 3 pregna-17a,20fi-di0l-17- acetate and 3a-(tetrahydropyran-2'-yloxy)-6a-trifluoromethyl-5fi-pregna-17a,20a-di0l-17-acetate.

In the same manner, the other 20-keto compounds of the present invention are converted into the corresponding ZO/E-hydroxy and 20a-hydroxy derivatives.

What is claimed is:

1. A compound selected from the group consisting of those of the Formulas A and C:

and

r R CH3 R1 wherein R is selected from the group consisting of o=o and o' R is selected from the group consisting of hydrogen, hydroxy, and a carboxylic acyloxy group of less than 12 carbon atoms;

R is selected from the group consisting of wherein R is selected from the group consisting of hydrogen, a carboxylic acyl group of less than 12. carbon atoms, tetrahydropyran-T-yl, and tetrahydrofuran-2-yl; and R is selected from the group consisting of on" x wherein R" is selected from the group consisting of tetrahydropyran-2'-yl and tetrahydrofuran-Z-yl.

2. A compound according to Formula A of claim 1 wherein R is C:O, R is a carboxylic acyloxy group of less than 12 carbon atoms and R is C=O.

3. A compound according to Formula A of claim 1 wherein R is C=O, and R is 4. A compound according to claim 3 wherein R hydrogen or tetrahydropyran-Z-yl and R is caproy-loxy.

7. A compound according to claim 3 wherein R hydrogen or tetrahydropyran-Z-yl and R is acetoxy.

8. A compound according to claim 3 wherein R hydrogen or tetrahydropyran-Z-yl and R is hydroxy.

9. A compound according to claim 3 wherein R hydrogen or tetrahydropyran-2-y-1 and R is hydrogen.

10. A compound according to Formula C of claim 1 wherein R is C=O and R is hydroxy.

11. A compound according to Formula C of claim 1 wherein R is C O and R is acetoxy.

12. A compound of Formula C of claim 1 wherein R is @O and R is caproyloxy.

13. A compound according to Formula A of claim 1 wherein R is References Qited UNITED STATES PATENTS 6/1967 Bowers et al. 260397.3 7/1967 Campbell et al. 260-397.4

ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 57, 59 Dated July 22, 1969 Inventor(s) John H. Fried It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

[- Column 5, line 21, the "on" should be deleted.

Column 6, line 22, after "-one, insert Boa-hydroxy- 6a-trifluoromethyl-S6-pregnan-20-one SIGNED AND SEALED JUL 281970 15 Atteat:

Edward M. Fletcher. I

WILLIAM u Officer 15- BGHUYLER Atws ng Commissioner 01 Pat nt s 

